The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease. Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be a high risk for the eventual development of the visual loss associated with glaucoma Some patients with glaucomatous field loss have relatively low intraocular pressure. These so called normotension or low tension glaucoma patients can also benefit from agents that lower and control IOP. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated. Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
There are some individuals who do not respond well when treated with certain existing glaucoma therapies. There is, therefore, a need for other topical therapeutic agents that control IOP.
It has been found that serotonergic compounds which possess agonist activity at 5-HT2 receptors effectively lower and control normal and elevated IOP and are useful for treating glaucoma, see commonly owned co-pending application, PCT/US99/19888. Compounds that act as agonists at 5-HT2 receptors are well known and have shown a variety of utilities, primarily for disorders or conditions associated with the central nervous system (CNS). U.S. Pat. No. 5,494,928 discloses certain 2-(indol-1-yl)-ethylamine derivatives that are 5-HT2C agonists for the treatment of obsessive compulsive disorder and other CNS derived personality disorders. U.S. Pat. No. 5,571,833 discloses tryptamine derivatives that are 5-HT2 agonists for the treatment of portal hypertension and migraine. U.S. Pat. No. 5,874,477 discloses a method for treating malaria using 5-HT2A/2C agonists. U.S. Pat. No. 5,902,815 discloses the use of 5-HT2A agonists to prevent adverse effects of NMDA receptor hypo-function. WO98/31354A2 discloses 5-HT2B agonists for the treatment of depression and other CNS conditions. WO00/12475 discloses indoline derivatives as 5-HT2B and 5-HT2C receptor agonists for the treatment of a variety of disorders of the central nervous system, but especially for the treatment of obesity. WO00/35922 discloses certain pyrazino[1 2-a]quinoxaline derivatives as 5-HT2C agonists for the treatment of obsessive-compulsive disorder, depression, eating disorders, and other disorders involving the CNS. Agonist response at the 5-HT2A receptor is reported to be the primary activity responsible for hallucinogenic activity, with some lesser involvement of the 5-HT2C receptor possible [Psychopharmacology, Vol. 121:357, 1995].
Certain pyrano[3,2-e]indol-3-ethylamines and the corresponding N,N-dimethylamino analogs have been reported in conjunction with serotonin receptor binding profile studies [J. Med. Chem. 35, 3625 (1992)]. These compounds have been shown to possess good affinity at the serotonin 5-HT2 receptor, though no utility has been associated with these compounds. The synthesis of other pyrano[3,2-e]indoles bearing a tertiary amine, either 3-[(N-methylpyrrolidin-2-yl)methyl] or 3-(N-methylpyrrolidin-3-yl), has been reported [Tetrahedron Lett. 35, 45 (1994)], but no utility was noted for these compounds. The rapid metabolic deamination of primary arylethylamines in general, and tryptamines in particular, by monoamine oxidase [Principles of Drug Action, 3rd Ed., p382 (1990)] is a significant impediment to the use of such compounds as therapeutic agents. It has been noted that this rapid oxidative deamination can be dramatically retarded or eliminated by the incorporation of an alkyl group on the carbon atom in the position alpha to the primary amine [Biotransformation of Xenobiotics, in Casaret & Doull's Toxicology, 5th ed., C. D. Klaassen Ed., pp. 129-145 (1996); Medicinal Res. Rev. 9, 45 (1989)]. Therefore, compounds bearing such an alpha alkyl group, such as those of the present disclosure, would be anticipated to provide a distinct therapeutic advantage.
Application EP 708,099 (1996) is concerned with the utility of selected pyrano[3,2-e]indoles as melatonin receptor agonists; and is, therefore, directed exclusively toward 3-(N-acyl-aminoalkyl)pyrano[3,2-e]indoles, that is non-basic amide derivatives, compounds that do not incorporate a basic primary amine, a functionality critical to the compounds of the present disclosure. U.S. Pat. No. 5,461,061 discloses certain unexampled 8-amino-pyrano[3,2-e]indol-1-alkylamines that are noted as selective 5-HT1A agonists useful for treating CNS disorders including depression, anxiety, senile dementia and obsessive compulsive disturbances. The indoline derivatives of U.S. Pat. No. 5,633,276 (1997), that is 1-(N-acyl-aminoethyl) furano- and pyrano[2,3-g]indole derivatives, are also non-basic compounds which are melatonin receptor modulators, most preferably agonists [J. Pharmacol. Exp. Ther. 285, 1239 (1998)], that are useful for the treatment of conditions associated with a disturbed melatonin system.